The goal of this proposal is to provide Christine lacobuzio-Donahue with a period of mentorship in the proper academic environment so that she can develop the necessary skills to become an independent clinician- scientist. In addition to her specialized training in gastrointestinal pathology, Dr. lacobuzio has a strong commitment to the study of pancreatic cancer metastasis. Pancreatic cancers are an almost universally fatal disease, with a 5 yr survival rate of 4%. This dismal prognosis is largely due to the fact that most patients are diagnosed with metastatic disease and all will die of metastatic disease within one year. Current surgical and chemotherapeutic approaches are beneficial only in the minority of patients who present with localized disease. The overall goal of this proposal is to provide a comprehensive understanding of metastatic pancreatic ductal adenocarcinomas that will form the basis for novel therapies designed with respect to the unique features of metastatic disease. To accomplish this goal, Dr. lacobuzio has already taken the unique and innovative approach to the study of pancreatic cancer metastasis by establishment of a rapid ("warm") autopsy protocol for procurement of high quality samples for study. These samples will be used for the generation of xenografted tumors and short-term cell cultures to provide an unparalleled resource for the planned studies. Next, Dr. lacobuzio will perform gene expression profiling of matched primary and metastatic pancreatic cancers to confirm potential biological markers identified in her prior studies of primary pancreatic cancers and to identify novel markers specific to metastatic disease. This approach will also aid Dr. lacobuzio in defining the "gene expression architecture" of metastatic pancreatic cancers with a particular focus on those cellular signalling pathways related to tumor-stromal interactions of the proliferating metastases within target organ sites. Finally, the potential markers identified will form the basis for creation of novel therapies specific to metastatic disease through Dr. lacobuzio's ongoing collaboration with the Drug Development Program at Johns Hopkins Medical Institutions. In summary, this proposal will provide the first in depth understanding of metastatic pancreatic cancer to form the basis for more focused studies aimed at the therapeutic development with immediate translational potential to pre-clinical trials.